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The abnormal lipid metabolism in diabetic cardiomyopathy can cause myocardial mitochondrial dysfunction, lipotoxicity, abnormal death of myocardial cells, and myocardial remodeling. Mitochondrial homeostasis and normal lipid metabolism can effectively slow down the development of diabetic cardiomyopathy. Recent studies have shown that SIRT6 may play an important role in the pathological changes of diabetic cardiomyopathy such as myocardial cell death, myocardial hypertrophy, and myocardial fibrosis by regulating mitochondrial oxidative stress and glucose and lipid metabolism. Therefore, understanding the function of SIRT6 and its role in the pathogenesis of diabetic cardiomyopathy is of great significance for exploring and developing new targets and drugs for the treatment of diabetic cardiomyopathy. This article reviews the latest findings of SIRT6 in the pathogenesis of diabetic cardiomyopathy, focusing on the regulation of mitochondria and lipid metabolism by SIRT6 to explore potential clinical treatments.
Assuntos
Diabetes Mellitus , Cardiomiopatias Diabéticas , Sirtuínas , Humanos , Cardiomiopatias Diabéticas/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Mitocôndrias/metabolismo , Sirtuínas/metabolismo , Diabetes Mellitus/metabolismoRESUMO
Cardiac cachexia is a deadly consequence of advanced heart failure that is characterised by the dysregulation of adipose tissue homeostasis. Once cachexia occurs with heart failure, it prevents the normal treatment of heart failure and increases the risk of death. Targeting adipose tissue is an important approach to treating cardiac cachexia, but the pathogenic mechanisms are still unknown, and there are no effective therapies available. Transcriptomics, metabolomics, and lipidomics were used to examine the underlying mechanisms of cardiac cachexia. Transcriptomics investigation of cardiac cachexia adipose tissue revealed that genes involved in fibrosis and monocyte/macrophage migration were increased and strongly interacted. The ECM-receptor interaction pathway was primarily enriched, as shown by KEGG enrichment analysis. In addition, gene set enrichment analysis revealed that monocyte chemotaxis/macrophage migration and fibrosis gene sets were upregulated in cardiac cachexia. Metabolomics enrichment analysis demonstrated that the sphingolipid signalling pathway is important for adipose tissue remodelling in cardiac cachexia. Lipidomics analysis showed that the adipose tissue of rats with cardiac cachexia had higher levels of sphingolipids, including Cer and S1P. Moreover, combined multiomics analysis suggested that the sphingolipid metabolic pathway was associated with inflammatory-fibrotic changes in adipose tissue. Finally, the key indicators were validated by experiments. In conclusion, this study described a mechanism by which the sphingolipid signalling pathway was involved in adipose tissue remodelling by inducing inflammation and fat fibrosis in cardiac cachexia.
Assuntos
Caquexia , Insuficiência Cardíaca , Ratos , Animais , Caquexia/genética , Caquexia/complicações , Esfingolipídeos/metabolismo , Multiômica , Tecido Adiposo/metabolismo , Fibrose , Insuficiência Cardíaca/patologia , Obesidade/metabolismoRESUMO
BACKGROUND: Astragalus polysaccharide (APS) is a key active ingredient isolated from Astragalus membranaceus that has been reported to be a potential treatment for obesity and diabetes by regulating lipid metabolism and adipogenesis, alleviating inflammation, and improving insulin resistance. However, whether APS regulates lipid metabolism in the context of cachexia remains unclear. Therefore, this study analysed the effects of APS on lipid metabolism and adipose expenditure in a heart failure (HF)-induced cardiac cachexia rat model. METHODS: A salt-sensitive hypertension-induced cardiac cachexia rat model was used in the present study. Cardiac function was detected by echocardiography. The histological features and fat droplets in fat tissue and liver were observed by H&E staining and Oil O Red staining. Immunohistochemical staining, Western blotting and RTâqPCR were used to detect markers of lipolysis and adipose browning in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Additionally, sympathetic nerve activity and inflammation in adipose tissue were detected. RESULTS: Rats with HF exhibited decreased cardiac function and reduced adipose accumulation as well as adipocyte atrophy. In contrast, administration of APS not only improved cardiac function and increased adipose weight but also prevented adipose atrophy and FFA efflux in HF-induced cachexia. Moreover, APS inhibited HF-induced lipolysis and browning of white adipocytes since the expression levels of lipid droplet enzymes, including HSL and perilipin, and beige adipocyte markers, including UCP-1, Cd137 and Zic-1, were suppressed after administration of APS. In BAT, treatment with APS inhibited PKA-p38 MAPK signalling, and these effects were accompanied by decreased thermogenesis reflected by decreased expression of UCP-1, PPAR-γ and PGC-1α and reduced FFA ß-oxidation in mitochondria reflected by decreased Cd36, Fatp-1 and Cpt1. Moreover, sympathetic nerve activity and interleukin-6 levels were abnormally elevated in HF rats, and astragalus polysaccharide could inhibit their activity. CONCLUSION: APS prevented lipolysis and adipose browning in WAT and decreased BAT thermogenesis. These effects may be related to suppressed sympathetic activity and inflammation. This study provides a potential approach to treat HF-induced cardiac cachexia.
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Tecido Adiposo Marrom , Insuficiência Cardíaca , Ratos , Animais , Tecido Adiposo Marrom/metabolismo , Caquexia/tratamento farmacológico , Caquexia/etiologia , Caquexia/prevenção & controle , Gastos em Saúde , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Inflamação/patologiaRESUMO
Fat loss predicts adverse outcomes in advanced heart failure (HF). Disrupted circadian clocks are a primary cause of lipid metabolic issues, but it's unclear if this disruption affects fat expenditure in HF. To address this issue, we investigated the effects of disruption of the BMAL1/REV-ERBα circadian rhythmic loop on adipose tissue metabolism in HF.50 Wistar rats were initially divided into control (n = 10) and model (n = 40) groups. The model rats were induced with HF via monocrotaline (MCT) injections, while the control group received equivalent solvent injections. After establishing the HF model, the model group was further subdivided into four groups: normal rhythm (LD), inverted rhythm (DL), lentivirus vector carrying Bmal1 short hairpin RNA (LV-Bmal1 shRNA), and empty lentivirus vector control (LV-Control shRNA) groups, each with 10 rats. The DL subgroup was exposed to a reversed light-dark cycle of 8 h: 16 h (dark: light), while the rest adhered to normal light-dark conditions (light: dark 12 h: 12 h). Histological analyses were conducted using H&E, Oil Red O, and Picrosirius red stains to examine adipose and liver tissues. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to detect markers of lipolysis, lipogenesis, and beiging of white adipose tissue (WAT), while thermogenesis indicators were detected in brown adipose tissue (BAT). The LD group rats exhibited decreased levels of BMAL1 protein, increased levels of REV-ERBα protein, and disrupted circadian circuits in adipose tissue compared to controls. Additionally, HF rats showed reduced adipose mass and increased ectopic lipid deposition, along with smaller adipocytes containing lower lipid content and fibrotic adipose tissue. In the LD group WAT, expression of ATGL, HSL, PKA, and p-PKA proteins increased, alongside elevated mRNA levels of lipase genes (Hsl, Atgl, Peripilin) and FFA ß-oxidation genes (Cpt1, acyl-CoA). Conversely, lipogenic gene expression (Scd1, Fas, Mgat, Dgat2) decreased, while beige adipocyte markers (Cd137, Tbx-1, Ucp-1, Zic-1) and UCP-1 protein expression increased. In BAT, HF rats exhibited elevated levels of PKA, p-PKA, and UCP-1 proteins, along with increased expression of thermogenic genes (Ucp-1, Pparγ, Pgc-1α) and lipid transportation genes (Cd36, Fatp-1, Cpt-1). Plasma NT-proBNP levels were higher in LD rats, accompanied by elevated NE and IL-6 levels in adipose tissue. Remarkably, morphologically, the adipocytes in the DL and LV-Bmal1 shRNA groups showed reduced size and lower lipid content, while lipid deposition in the liver was more pronounced in these groups compared to the LD group. At the gene/protein level, the BMAL1/REV-ERBα circadian loop exhibited severe disruption in LV-Bmal1 shRNA rats compared to LD rats. Additionally, there was increased expression of lipase genes, FFA ß oxidation genes, and beige adipocyte markers in WAT, as well as higher expression of thermogenic genes and lipid transportation genes in BAT. Furthermore, plasma NT-proBNP levels and adipose tissue levels of NE and IL-6 were elevated in LV-Bmal1 shRNA rats compared with LD rats. The present study demonstrates that disruption of the BMAL1/REV-ERBα circadian rhythmic loop is associated with fat expenditure in HF. This result suggests that restoring circadian rhythms in adipose tissue may help counteract disorders of adipose metabolism and reduce fat loss in HF.
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Fatores de Transcrição ARNTL , Insuficiência Cardíaca , Ratos , Animais , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Monocrotalina , Gastos em Saúde , Interleucina-6/metabolismo , Ratos Wistar , Ritmo Circadiano/genética , Tecido Adiposo Marrom/metabolismo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Lipase/metabolismo , RNA Interferente Pequeno/metabolismo , LipídeosRESUMO
Objectives: The incidence of vascular dementia (VaD) is steadily rising annually, significantly impacting the mental well-being and overall quality of life of the elderly, and imposing substantial economic burdens on families and society. In recent years, non-pharmacological therapies as supplementary treatments for VaD have garnered significant attention and have been extensively utilized in clinical settings. Consequently, a network meta-analysis (NMA) was conducted by us to assess the effectiveness of various non-pharmacological therapies in the management of VaD. Design: We systematically searched seven databases from their inception up to January 2024 to identify randomized controlled trials focusing on non-pharmacological interventions for the treatment of VaD. The methodological quality and risk of bias were rigorously assessed utilizing the RoB 2.0 evaluation tool. The NMA was performed using R software and STATA 14 software, adhering to frequentist theory principles. Additionally, sensitivity analysis, meta-regression analysis, and funnel plot were conducted to assess the stability, heterogeneity, and publication bias, respectively. Results: The NMA included 91 eligible studies involving 7,657 patients. The NMA results indicated that in terms of improving Mini-Mental State Examination (MMSE), the following non-pharmacological interventions ranked higher based on p-value: acupuncture_moxibustion_ conventional treatment (ACUP_MB_CT) [P-score = 0.95; pooled mean difference (95% CI): 5.09 (3.82; 6.36)], fastigial nucleus stimulation_CT (FNS_CT) [0.87; 4.51 (2.59; 6.43)], ACUP_rehabilitation training_CT (ACUP_RT_CT) [0.84; 4.19 (2.77; 5.61)], repetitive transcranial magnetic stimulation_CT (rTMS_CT) [0.82; 3.98 (3.08; 4.88)], and aerobic exercise_CT (AE_CT) [0.82; 4.25 (1.86; 6.64)]. Regarding improvement in Activities of Daily Living Scale (ADL), the following non-pharmacological interventions ranked higher based on P-score: ACUP_MB_CT [0.98; 17.21 (13.19; 21.23)], ACUP_RT_CT [0.87; 14.32 (8.43; 20.22)], rTMS_CT [0.78; 11.83 (9.92; 13.75)], and ACUP_CT [0.73; 11.23 (9.26; 13.19)]. No significant adverse reactions were reported in the included studies. Conclusion: ACUP_MB_CT may be considered the most efficacious intervention for enhancing cognitive function and daily living skills in individuals diagnosed with VaD. Furthermore, ACUP_RT_CT, rTMS_CT, FNS_CT, ACUP_CT, and AE_CT also demonstrate significant clinical utility. Non-pharmacological interventions are unlikely to significantly increase adverse reactions and has a certain degree of safety.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier [CRD42024498902].
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BACKGROUND: Huangqi Guizhi Wuwu decoction (HQGZWWD) is a traditional Chinese herbal medicine formulation with significant anti-inflammatory activity. However, its underlying mechanism remains unknown. Through network pharmacology and experimental validation, this study aimed to examine the potential mechanism of HQGZWWD in regulating macrophage polarization and inflammation. METHODS: The active components were obtained from the Traditional Chinese Medicine Systems Pharmacology database and Analysis Platform (TCMSP), whereas the corresponding targets were obtained from the TCMSP and Swiss Target Prediction database. The GeneCards database identified targets associated with macrophage polarization and inflammation. Multiple networks were developed to identify the key compounds, principal biological processes, and pathways of HQGZWWD that regulate macrophage polarization and inflammation. Autodock Vina is utilized to assess the binding ability between targets and active compounds. Finally, confirm the experiment's central hypothesis. Human histiocytic lymphoma (U-937) cells were transformed into M1 macrophages following stimulation with Lipopolysaccharide (LPS) to evaluate the effect of HQGZWWD drug-containing mouse serum (HQGZWWD serum) on regulating macrophage polarization and inflammation. RESULTS: A total of 54 active components and 859 HQGZWWD targets were obtained. There were 9972 targets associated with macrophage polarization and 11,109 targets associated with inflammation. After screening, 34 overlapping targets were identified, of which 5 were identified as central targets confirmed by experiments, including the α7 nicotinic acetylcholine receptor (α7 nAchR), interleukin 6 (IL-6), Interleukin-1 beta (IL-1ß), interleukin 10 (IL-10) and growth factor beta (TGF-ß1). Pathway enrichment analysis revealed that 34 overlapping targets were enriched in multiple pathways associated with macrophage polarization and inflammation, including the TGF beta signaling pathway, NF-kappa B signaling pathway, JAK-STAT signaling pathway, and TNF signaling pathway. Molecular docking confirmed that the majority of HQGZWWD's compounds can bind to the target. In vitro experiments, HQGZWWD serum was shown to up-regulate the expression of α7 nAchR, reduce the number of M1 macrophages, stimulate the production of M2 macrophages, inhibit the expression of pro-inflammatory cytokines IL-6 and IL1-ß, and increase the expression of anti-inflammatory cytokines IL-10 and TGF-ß1. CONCLUSION: HQGZWWD can regulate the number of M1/M2 macrophages and the level of inflammatory cytokines, and the underlying mechanism may be related to the up-regulation of α7 nAchR expression.